Combinatorial library of moenomycin analogs and methods of producing same

Abstract

A combinatorial chemical library of compounds structurally related to the moenomycin class of antibiotics has the formula ##STR1## wherein D is a donor mono- or disaccharide, A is an acceptor monosaccharide, and P-R is a lipophosphoglycerate mimetic group. Members of the library have a glycosidic linkage between the anomeric carbon of D and the C2 carbon of A, and the D-A moiety is in turn covalently linked through the anomeric carbon of A to the P-R group. Members of the library exhibit their greatest structural diversity in terms of substitutions occurring at the C3 position of the A residue, substitutions at the C2 position of the D residue, and different P-R groups used in assembling the compounds. Members of the library are preferably synthesized by solid phase techniques involving stepwise coupling of the respective units to a support, functionalizing the A and/or D saccharides either before or after immobilizing them on the support, and cleaving the assembled compounds from the support. Preferred functionalities attached to the sugar residues are amides, carbamates, ureas, sulfonamides, substituted amines, esters, carbonates, and sulfates. Exemplary P-R groups are derivatives of homoserine, glyceric acid, salicylates and mandelic acid. Members of the library can be screened for anti-microbial activity by contacting them with a culture of microbes and monitoring the growth rate of the microbes.

What is claimed is: 
     
       1. A compound having the formula ##STR37## wherein D represents a monosaccharide or disaccharide, A represents a monosaccharide, and P-R represents a lipophosphoglycerate mimetic group that is not a phospholipid group of moenomycin A or a saturated form thereof, wherein the anomeric carbon atom of D is covalently linked to the C2 carbon atom of A through a glycosidic linkage and the anomeric carbon atom of A is covalently bonded to P-R through an oxygen atom, and wherein the lipophosphoglycerate mimetic group has at least two electronegative substituents, two of which can release a proton. 
     
     
       2. The compound of claim 1, wherein A represents a pyranosiduronic acid, a pyranosiduronamide, a furanosiduronic acid, or a furanosiduronamide. 
     
     
       3. The compound of claim 1, wherein A is an α or β isomer of a D or L form of a glucopyranosiduronamide, a galactosiduronamide, a 4-C-methyl-glucopyranosiduronamide, a 4-C-methyl-galactopyranosiduronamide, a 3-amino-3-deoxy analog thereof, or an epimer thereof. 
     
     
       4. The compound of claim 1, wherein A has a formula selected from the group consisting of: ##STR38## wherein R 3  is X--Y, where X is O-- or NH--, and Y is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, C(O)R, C(O)NHR, C(O)OR, or SO 2  R, where R is H, alkyl, cycloalkyl, alkenyl, aryl, alkaryl, or heterocycle, or X--Y combine to form N 3  ; R 4  is O--X, where X is H, alkyl, cycloalkyl, alkenyl, acyl, benzoyl, aryl or aralkyl; and   R 6  is OH, NH 2 , or NHMe.   
     
     
       5. The compound of claim 1, wherein D is an α or β isomer of a D or L form of a glucopyranoside, a galactopyranoside, a mannopyranoside, a fucopyranoside, or an epimer thereof. 
     
     
       6. The compound of claim 1, wherein D has a formula selected from the group consisting of: ##STR39## wherein R 2  is X--Y, where X is O-- or NH--, and Y is H, alkyl, cycloalkyl, alkenyl, C(O)R, C(O)NHR, C(O)OR, or SO 2  R, where R is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or X--Y combine to form N 3 , or phthalimido; R 3  is X--Y, where X is O-- or NH--, and Y is H, alkyl, cycloalkyl, alkenyl, C(O)R, C(O)NHR, C(O)OR, or SO 2  R, where R is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or X--Y combine to form N 3 , phthalimido, or a monosaccharide residue;   R 4  is X--Y, where X is O-- or NH--, and Y is H, alkyl, cycloalkyl, alkenyl, C(O)R, C(O)NHR, C(O)OR, or SO 2  R, where R is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or X--Y combine to form N 3 , phthalimido, or a monosaccharide residue, or R 3  and R 4  combine to form carbonato; and   R 6  is H or X--Y, where X is O-- or NH--, and Y is H, alkyl, cycloalkyl, alkenyl, C(O)R, C(O)NHR, C(O)OR, or SO 2  R, where R is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or X--Y combine to form N 3 , phthalimido, or a monosaccharide residue.   
     
     
       7. The compound of claim 1, wherein the P-R group contains at least two electronegative functionalities independently selected from the group consisting of phosphate, phosphoanhydride, phosphonate, sulfonate, carboxylate, hydroxyl, hydroxylamine, and acylsulfonamido groups. 
     
     
       8. The compound of claim 7, wherein first and second electronegative functionalities are separated through space at a distance of 2.5 to 10 angstroms. 
     
     
       9. The compound of claim 7, wherein first and second electronegative functionalities are separated from each other by 1 to 8 chemical bonds. 
     
     
       10. The compound of claim 7, wherein A-P-R is represented by one of the following formulas: ##STR40## wherein W═O, CH 2 , O--CH 2  --, or --CH 2  --CH 2  --; X is a single bond, CH 2 , O, NH, or S;   Y═O, NH, S, or CH;   Z═H, halogen, or NO 2  ;   R is H, alkyl, cycloalkyl, alkenyl, acyl, benzoyl, aryl, aralkyl, or such group substituted with at least one heteroatom;   m is an integer of 0-2;   n is an integer of 0-2; or a position isomer thereof.   
     
     
       11. A combinatorial chemical library of moenomycin analog compounds comprising a plurality of the compounds of claim 1. 
     
     
       12. A method of screening a compound of claim 1 for anti-microbial activity, comprising contacting said compound with a culture of microbes, and monitoring the growth rate or inhibition of peptidoglycan synthesis of the microbes. 
     
     
       13. The compound of claim 1, wherein A has a formula selected from the group consisting of: ##STR41## D has a formula selected from the group consisting of: ##STR42## wherein R 2  is X--Y, where X is O-- or NH--, and Y is H, alkyl, cycloalkyl, alkenyl, C(O)R, C(O)NHR, C(O)OR, or SO 2  R, where R is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or X--Y combine to form N 3 , or phthalimido; R 3  is X--Y, where X is O-- or NH--, and Y is H, alkyl, cycloalkyl, alkenyl, C(O)R, C(O)NHR, C(O)OR, or SO 2  R, where R is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or X--Y combine to form N 3 , phthalimido, or a monosaccharide residue;   R 4  is X--Y, where X is O-- or NH--, and Y is H, alkyl, cycloalkyl, alkenyl, C(O)R, C(O)NHR, C(O)OR, or SO 2  R, where R is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or X--Y combine to form N 3 , phthalimido, or a monosaccharide residue, or R 3  and R 4  combine to form carbonato; and   R 6  is H or X--Y, where X is O-- or NH--, and Y is H, alkyl, cycloalkyl, alkenyl, C(O)R, C(O)NHR, C(O)OR, or SO 2  R, where R is H, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, or heterocycle, or X--Y combine to form N 3 , phthalimido, or a monosaccharide residue;   and A-P-R is represented by one of the following formulas: ##STR43##  wherein W═O, CH 2 , O--CH 2  --, or --CH 2  --CH 2  --; X is a single bond, CH 2 , O, NH, or S;   Y═O, NH, S, or CH;   Z═H, halogen, or NO 2  ;   R is H, alkyl, cycloalkyl, alkenyl, acyl, benzoyl, aryl, aralkyl, or such group substituted with at least one heteroatom;   m is an integer of 0-2;   n is an integer of 0-2; or a position isomer thereof.